Biology is the study of complex systems whose components are regulated not only in their ability to interact, but at the level of their synthesis and degradation. Interdependencies between components in both types of reactions are the norm rather than the exception. A hallmark of Systems Biology is the focus on understanding the behavior of the biological system following the identification of all relevant components. Mathematical modeling has been essential in other complex Systems studies, and has been successfully applied to biological systems at many different scales to elucidate systems emergent properties in many different applications. However, key challenges remain in making mathematical modeling approaches as impactful in biology as it ought to be. These challenges are conceptual, technical, and cultural. The Mathematical Modeling Core will address barriers that have hindered the widespread incorporation of modeling tools into biomedical research through a series of Research Activities and Service Activities.